Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of ß3-adrenergic receptors (ß3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel ß3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of ß3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full ß3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a ß3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel ß3AR agonist probe, [3H]MRL-037, that selectively labels ß3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of ß3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Surviving the sex trade: a comparison of HIV risk behaviours among street-involved women in two Canadian cities who inject drugs.

In Canada, very little is known about the factors and processes that cause drug-related harm among female intravenous drug users (IDUs). Women who inject drugs and participate in the survival sex trade are considered to be at increased risk for sexual and drug-related harms, including HIV infection. Between September 1999 and September 2000, women participating in the VIDUS cohort in Vancouver and the St. Luc Cohort in Montreal completed interviewer-administered questionnaires. Analyses were conducted to compare the demographic characteristics, sexual risk behaviours, risky injection practices and drug use patterns among women who self-identified as participating in the sex trade with those who did not identify as participating in the sex trade. Logistic regression was used to identify factors independently associated with exchanging sex for money or drugs. HIV prevalence at the study visit (September 1999-2000) was 29% for sex trade workers and 29.2% for non-sex trade workers. While patterns of sexual risk were similar, the risky injection practice and drug use patterns between sex trade workers and non-sex trade workers were markedly different. Logistic regression analysis of cross-sectional data revealed that independent behaviours associated with the sex trade included: greater than once per day use of heroin (adjusted OR 2.7), smokeable crack cocaine (adjusted OR = 3.3) and borrowing used syringes (adjusted OR = 2.0). Creative, client-driven interventions are urgently needed for women who trade sex for money or for drugs.

High pregnancy rates and reproductive health indicators among female injection-drug users in Vancouver, Canada.

OBJECTIVE: To determine the incidence of pregnancy among active injection-drug users and to identify factors associated with becoming pregnant. METHODS: The Vancouver Injection Drug User Study (VIDUS) is a prospective cohort study that began in 1996. Women who had completed a baseline and at least one follow-up questionnaire between June 1996 and January 2002 were included in the study. Parametric and non-parametric methods were used to compare characteristics of women who reported pregnancy over the study period with those who did not over the same time period. RESULTS: A total of 104 women reported a primary pregnancy over the study period. The incidence of pregnancy over the follow-up period was 6.46 (95% confidence interval (CI) 5.24-7.87) per 100 person-years. The average age of women who reported pregnancy was younger than that of women who did not report pregnancy (27 vs. 32 years, p < 0.001). Women of Aboriginal ethnicity were more likely to report pregnancy (odds ratio 1.6, 95% CI 1.0-2.5). Comparison of drug use showed no significant differences in pregnancy rate with respect to the use of heroin, cocaine or crack (p > 0.05). In examining sexual behavior, women who reported having had a regular partner in the previous 6 months were three times more likely to have reported pregnancy. Despite the fact that 67% of women in this study reported using some form of contraception, the use of reliable birth control was low. Only 5% of women in our study reported the use of hormonal contraceptives. CONCLUSION: There were a high number of pregnancies among high-risk women in this cohort. This corresponded with very low uptake of reliable contraception. Innovative strategies to provide reproductive health services to at-risk women who are injecting drugs is a public health priority.

A demographic and health profile of gay and bisexual men in a large Canadian urban setting.

The purpose of this study was to provide both a population estimate and a socio-economic and health profile of gay and bisexual men living with HIV/AIDS in a large Canadian urban centre. A random telephone survey was used to determine the number of men in the study area over the age of 20 identifying as gay or bisexual and to characterize their health and socio-economic status. Out of a total of 1,176 completed interviews, 300 males described themselves as gay or bisexual. Projecting this figure on recent census data we estimated the number of men identifying as gay or bisexual in this region of downtown Vancouver, BC, at 5,100. Among these men we found an HIV prevalence rate of 16%, with those who reported a positive serostatus being less likely to be employed full time and more likely to earn less than $20,000 per year. In terms of clinical characteristics, HIV-positive men had a median CD4 cell count of 397 cells/mm(3) and a median viral load of less than 500 copies/ml. Eighty-three per cent of the HIV-positive respondents were on antiretroviral therapy and the median number of drugs taken by these men was three. In summary, random surveys of populations affected by this epidemic are important for policy makers, clinicians and persons caring for those with HIV/AIDS as they paint a clearer picture of who is being affected and help to identify areas where increased services are needed.

Risk factors associated with HIV infection among young gay and bisexual men in Canada.

OBJECTIVE: To assess risk factors associated with HIV prevalence and incidence among gay and bisexual men in two prospective Canadian cohorts. METHODS: The Vanguard Project and the Omega Cohort are prospective cohort studies of gay and bisexual men ongoing in Vancouver and Montreal, respectively. For this analysis, baseline sociodemographic characteristics, sexual behavior, and substance use data from these two cohorts were combined. Assessment of risk factors for HIV seroprevalence and seroconversion were carried out using univariate and multivariate analysis. RESULTS: This analysis was based on 1373 gay and bisexual men aged 16 to 30 years. Men who were HIV-seropositive at baseline (n = 48) were more likely to report living in unstable housing, to have had less than a high school education, and to have been unemployed than those who were HIV-negative (n = 1325). HIV-positive men were also more likely to report having engaged in sexual risk behavior, including having had consensual sex at a younger age, having had at least 6 partners during the previous year, ever having been involved in the sex trade, and having engaged in unprotected receptive anal intercourse. With respect to substance use, HIV-positive men were more likely to report the use of crack, cocaine, heroin, and marijuana and to use injection drugs. Similarly, men who seroconverted during the course of the studies (n = 26) were more likely to report having less than a high school education and having lived in unstable housing at baseline. Compared with HIV-negative men, men who seroconverted were more likely to report ever having been involved in the sex trade and engaging in unprotected receptive anal intercourse. Reports of cocaine use and injection drug use were also significantly higher for men who seroconverted compared with HIV-negative men. CONCLUSIONS: Our data indicate that HIV-positive gay and bisexual men are more likely to be living in unstable conditions and to report more risky sexual and substance use behaviors than HIV-negative men.

Longitudinal patterns of sexual behavior and condom use in a cohort of HIV-negative gay and bisexual men in Vancouver, British Columbia, Canada, 1995-2000.

OBJECTIVE: To characterize longitudinal patterns of sexual behavior in a cohort of young gay and bisexual men and determine their reasons for not using condoms. METHODS: Prospective data from a cohort of young gay and bisexual men aged 18 to 30 years were studied. Study participants had completed a baseline questionnaire and HIV test between May 1995 and April 1996 and four annual follow-up questionnaires. RESULTS: A total of 130 HIV-negative Vanguard participants met the eligibility criteria for this analysis. The median age at baseline was 26 years (range, 24-28). Most were white (79%), had completed high school (85%), were currently employed (82%), lived in stable housing (95%), and reported annual incomes of > or =$10,000 (82%). (All dollar amounts are given in Canadian dollars.) Consistently over the 5-year study period, > 70% of study subjects reported having > or =1 regular male sexual partners in the previous year. During each of the five successive 1-year periods, between 34% and 40% of respondents reported having had unprotected receptive anal intercourse with regular partners. Slightly fewer individuals (between 29%-39%) reported having had unprotected insertive anal intercourse with regular partners. Between 13% and 25% of participants reported having had insertive unprotected anal intercourse with casual sexual partners; and between 9% and 18% reported having had unprotected receptive anal intercourse with casual sexual partners. Reasons for engaging in unprotected anal intercourse varied depending on type of sexual partnership. CONCLUSION: High-risk sexual behaviors remained fairly consistent over a 5-year period in this study. This suggests that it is critically important to understand the motivations for unprotected sex when designing and implementing programs aimed at reducing HIV risk among young gay and bisexual men.

Increasing incidence of HIV infections among young gay and bisexual men in Vancouver.

Since the beginning of the HIV epidemic in north America, the majority of HIV infections have occurred among men who engage in sexual relations with other men. As the HIV epidemic enters its third decade, gay and bisexual men continue to have among the highest rates of HIV infection. Previous studies have highlighted the decline in the incidence of HIV and risk behaviour among gay and bisexual men. However, several studies have suggested that young gay and bisexual men continue to engage in unprotected sexual behaviours and are at continued risk of HIV infection. Recent reports in the media and research literature have indicated an increase in the incidence of HIV among gay and bisexual individuals in many of the world's major cities. The purpose of this study was to determine trends in HIV incidence using data from a prospective cohort of young gay and bisexual men.

Initial structure-activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-arylindoles.

A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.

Beta(3)-adrenoceptor agonist-induced increases in lipolysis, metabolic rate, facial flushing, and reflex tachycardia in anesthetized rhesus monkeys.

The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and cardiovascular function were studied in anesthetized rhesus monkeys. Both compounds are potent and specific agonists at human and rhesus beta(3)-adrenergic receptors. Intravenous administration of either compound produced dose-dependent lipolysis, increase in metabolic rate, peripheral vasodilatation, and tachycardia with no effects on mean arterial pressure. The increase in heart rate in response to either compound was biphasic with an initial rapid component coincident with the evoked peripheral vasodilatation and a second more slowly developing phase contemporaneous with the evoked increase in metabolic rate. Because both compounds exhibited weak binding to and activation of rhesus beta(1)-adrenergic receptors in vitro, it was hypothesized that the increase in heart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta(1)-adrenergic receptors. This hypothesis was confirmed by determining that beta(3)-adrenergic receptor agonist-evoked tachycardia was attenuated in the presence of propranolol and in ganglion-blocked animals, under which conditions there was no reduction in the evoked vasodilatation, lipolysis, or increase in metabolic rate. It is not certain whether the beta(3)-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at beta(3)-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to beta(3)-adrenergic receptor agonist administration was not attenuated in animals administered mepyramine, indomethacin, or calcitonin gene-related peptide(8-37). These findings are consistent with a direct vasodilator effect of beta(3)-adrenergic receptor agonists.

Human beta3 adrenergic receptor agonists containing cyanoguanidine and nitroethylenediamine moieties.

Pyridineethanolamine derivatives containing cyanoguanidine or nitroethylenediamine moieties were examined as human beta3 adrenergic receptor (AR) agonists. Notably, indoline derivatives 6a and 11 were potent beta3 AR agonists (beta3 EC50 = 13 and 19 nM, respectively), which showed good selectivity over binding to and minimal activation of the beta1 and beta2 ARs.

Sex trade involvement and rates of human immunodeficiency virus positivity among young gay and bisexual men.

BACKGROUND: Susceptibility to human immunodeficiency virus (HIV) infection is of particular concern for marginalized populations. The objective of this study was to determine risk factors associated with sex trade work among young gay and bisexual men. Further, we aimed to compare HIV prevalence and incidence among men involved and not involved in sex trade work. METHODS: The study is based upon data obtained from a prospective cohort study of young gay and bisexual men. Participants had completed a baseline questionnaire which elicited information on demographic information, sexual behaviours, and substance use. Sex trade involvement was defined as the exchange of money, drugs, goods, clothing, shelter or protection for sex within the one year prior to enrollment. Contingency table and multivariate logistic regression analyses were used to identify risk factors associated with involvement in the sex trade. RESULTS: Of the 761 eligible participants, 126 (16%) reported involvement in sex trade work. Multivariate logistic regression analysis revealed regular alcohol use (Odds Ratio [OR] = 3.6, 95% CI : 1.8-7.2), aboriginal ethnicity (OR = 3.7, 95% CI : 1.6-8.7), unemployment (OR = 3.9, 95% CI : 2.1-7.3), history of residence in a psychiatric ward (OR = 4.2, 95% CI : 1.8-9.8), bisexual activity (OR = 7.0, 95% CI : 3.5-14.1) and the use of crack (OR = 7.4, 95% CI : 3.0-18.7) to be independently associated with sex trade work. Sex trade workers had a significantly higher HIV prevalence at baseline compared with non-sex trade workers (7.3% versus 1.1%, P < 0.001). As well, HIV incidence was found to be significantly higher for sex trade workers compared with non-sex trade workers (4.7% versus 0.9%, P = 0.011). CONCLUSION: Our study reveals that for male sex trade workers in this setting increased vulnerability to HIV infection is related to unfavourable living conditions, substance use and sexual risk behaviour.

L-750355, a human beta3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey.

The profile of in vitro and in vivo biology of a human beta3-adrenoceptor agonist, (S)-N-[4-[2-[[3[(2-amino-5-pyridinyl)oxy]-2-hydroxy-propyl]amino]-eth yl]-phenyl]-4-isopropylbenzenesulfonamide, L-750355, is described. Using cloned human and rhesus beta1-, beta2- and beta3-adrenoceptors, expressed in Chinese hamster ovary (CHO) cells, L-750355 was shown to be a potent, albeit partial, agonist for the human (EC(50)=10 nM; % maximal receptor activation=49%) and rhesus (EC(50)=28 nM; % maximal receptor activation=34%) beta3-adrenoceptors. Furthermore, L-750355 stimulates lipolysis in rhesus adipocytes in vitro. L-750355 is a weak partial agonist (EC(50)=3.2 microM; % maximal receptor activation=33% ) for the human beta1-adrenoceptor but exhibits no agonist activity for rhesus beta1- or beta2-adrenoceptors of either human or rhesus origin. Administration of L-750355 to anesthetized rhesus monkeys, as a series of rising dose intravenous infusions, evokes dose-dependent glycerolemia and tachycardia with no change in mean arterial blood pressure or plasma potassium. The dose-response curve for L-750355-induced glycerolemia lies to the left of that for tachycardia. Propranolol, at a dose (0.3 mg/kg, i.v. ) that attenuates isoproterenol-induced changes in heart rate and glycerolemia, abolished L-750355-induced tachycardia but had no effect on L-750355-induced glycerolemia.

Discovery of a potent, orally bioavailable beta(3) adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4 -[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide.

As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.

Tetrahydroisoquinoline derivatives containing a benzenesulfonamide moiety as potent, selective human beta3 adrenergic receptor agonists.

Tetrahydroisoquinoline derivatives containing a 4-(hexylureido)benzenesulfonamide were examined as human beta3 adrenergic receptor (AR) agonists. Notably, 4,4-biphenyl derivative 9 was a 6 nM full agonist of the beta3 AR. Naphthyloxy compound 18 (beta3 EC50 = 78 nM) did not activate the beta1 and beta2 ARs at 10 microM, and showed >1000-fold selectivity over binding to the beta1 and beta2 ARs.

Potent, selective 3-pyridylethanolamine beta3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore.

A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.

Human beta3-adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides.

Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.

Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists.

As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.

Discovery of an orally bioavailable alkyl oxadiazole beta3 adrenergic receptor agonist.

5-n-Pentyl oxadiazole substituted benzenesulfonamide 8 is a potent and selective beta3 adrenergic receptor agonist (beta3 EC50 = 23 nM, beta1 IC50 = 3000 nM, beta2 IC50 = 3000 nM). The compound has high oral bioavailability in dogs (62%) and rats (36%) and is among the most orally bioavailable beta3 adrenergic receptor agonists reported to date.

Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents.

Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.

Determinants of hospital admission among HIV-positive people in British Columbia.

BACKGROUND: This study was initiated to evaluate the demographic and clinical determinants of admission to hospital among HIV-positive men and women receiving antiretroviral therapy in British Columbia. METHODS: The analysis was restricted to participants enrolled in the HIV/AIDS Drug Treatment Program between September 1992 and March 1997 who had completed an annual participant survey, had a viral load determination and had signed a consent form allowing electronic access to their inpatient hospital records. A record linkage was conducted with the BC Ministry of Health to obtain all records of hospital admissions from April 1991 to March 1997. Statistical analyses were carried out using parametric and nonparametric methods and multivariate logistic analyses. RESULTS: The study sample comprised 947 participants (859 men, 88 women). Of these, 165 (17%) were admitted to hospital during the study period from May 1, 1996, to Mar. 31, 1997. The median number of admissions was 1 (interquartile range [IQR] 1-2 admissions), and the median length of stay per admission was 3 days (IQR 1-8 days). Admission to hospital was associated with being unemployed (82% of those admitted v. 58% of those not admitted), being an injection drug user (24% v. 17%), reporting a fair or poor health status (46% v. 29%) and having a physician experienced in the management of HIV/AIDS (31% v. 24%). Examination of clinical determinants demonstrated that hospital admission was associated with a previous admission (72% v. 46%), a high viral load (median 74,000 v. 14,000 HIV-1 RNA copies/mL), a low CD4 count (median 0.16 v. 0.27 x 10(9)/L) and an AIDS diagnosis (44% v. 24%). Multivariate logistic regression analysis revealed that being admitted to hospital was independently associated with being unemployed (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.66-4.20), having been previously admitted to hospital (OR 2.30, 95% CI 1.53-3.46), having a high viral load at baseline (OR 1.45, 95% CI 1.16-1.80), being an injection drug user (OR 1.63, 95% CI 1.02-2.62) and having an experienced physician (OR 1.98, 95% CI 1.29-3.03). INTERPRETATION: Hospital admission among participants in this study was found to be associated with marginalization and poor health status.